Cores for technetium radiopharmaceuticals

ABSTRACT

A synth  99m  Tc complex which contains the moiety Tc═NR, Tc--N═NY or Tc(--N═NY) 2  and an organic ligand which confers biological target-seeking properties on the technetium complex, where R is an aryl group, a substituted or unsubstituted alkyl group or the group --NR 1  R 2  ; Y is an aryl group or a substituted or unsubstituted alkyl group; and R 1  and R 2  are H, aryl groups or substituted or unsubstituted aliphatic or cyclic alkyl groups, and are the same or different provided that both are not hydrogen. Radiopharmaceuticals comprising this complex are also described, together with methods for the preparation of the complex.

This is a divisional application of Ser. No. 08/289,654, filed Aug. 12, 1994 now U.S. Pat. No. 5,589,576; which is a continuation of Ser. No. 07/689,763, filed May 29, 1991 now abandoned, which is a 371 of PCT/GB90/01330, filed Aug. 28, 1990.

This invention relates to novel complexes of technetium (Tc), containing the moiety Tc═NR, Tc--N═NY or Tc(--N═NY)₂, and their use in radiopharmaceuticals for a variety of clinical applications. Methods for the preparation of the technetium complexes are also described.

Radiopharmaceuticals may be used as diagnostic or therapeutic agents by virtue of the physical properties of their constituent radionuclides. Thus, their utility is not based on any pharmacologic action. Most clinically used drugs of this class are diagnostic agents incorporating a gamma-emitting nuclide which, because of physical or metabolic properties of its co-ordinated ligands, localises in a specific organ after intravenous injection. The resultant images can reflect organ structure or function. These images are obtained by means of a gamma camera that detects the distribution of ionising radiation emitted by the radioactive molecules. The principal isotope currently used in clinical diagnostic nuclear medicine is metastable technetium-99m (^(99m) Tc) and which has a half-life of 6 hours.

The preparation of ^(99m) Tc radiopharmaceuticals generally requires addition of generator-produced Na^(99m) TcO₄ eluate to a ligand or ligands in the presence of a reducing agent. Many reducing agents have been used to this effect including tin metal, stannous ion, sodium borohydride, ferrous ascorbate, ferrous ion and formamidine sulphonic acid. These procedures often lead to Tc complexes containing the Tc═O moiety, where the technetium is in the +4 or +5 oxidation state. The formation of such radiopharmaceutical complexes can often occur via substitution reactions on [Tc^(V) OX₅ ]²⁻ or [Tc ^(IV) X₆ ]²⁻ molecules, which has been identified as a route of significant synthetic utility (Deutsch E, Libson K, Jurisson S, Lindoy L F, Technetium Chemistry and Technetium Radiopharmaceuticals, Prog. Inorg. Chem. (1982) 30 p 175). Only under harsh reaction conditions in the presence of powerful reducing agents and/or strong acids or bases are Tc^(I) oxidation state complexes attained and stabilised. A limitation to the formation of novel radiopharmaceutical products is the tendency towards formation of Tc═O species, but in addition formation of Tc⁴⁺ or Tc⁵⁺ complexes also limits the number and/or type of ligands prone to bind to the metal.

PCT Application WO 85/03063 describes the synthesis of the Tc═N moiety as an intermediate in the preparation of radiopharmaceuticals by virtue of its ability to undergo various ligand substitution reactions. The Tc═N core is again primarily based on the +5 oxidation state of Tc.

The reaction of TcCl₆ ²⁻ with hydroxylamine salts under a variety of conditions to form a variety of complexes containing the Tc--NO moiety has been described (Eakins, J C S (1963) 6012; Radnovich and Hoard, J. Phys. Chem. 88 (26) (1984) 6713; Armstrong and Taube, Inorg. Chem. (1976) 15 (3), 1904). This literature is concerned with ⁹⁹ Tc and not with its metastable isotope ^(99m) Tc. ⁹⁹ Tc has a half-life of 2.1×10⁵ years, decays by emitting beta particles, and is of no interest as a radiopharmaceutical.

European Patent Application No. 0 291 281 A describes technetium complexes containing the ^(99m) Tc--NO moiety, together with a ligand which confers biological target-seeking properties on the complex, and their use as radiopharmaceuticals. The complexes are made from pertechnetate (TcO₄ ⁻) by a variety of routes involving hydroxylamine salts. Studies of the coordination chemistry of technetium have generally been directed towards the synthesis and development of new ^(99m) Tc labelled radiopharmaceuticals. ¹ The majority of the technetium containing radiopharmaceuticals currently in clinical use involve technetium complexes containing either a mono-oxo or di-oxo core, i.e. [Tc^(V)═O]³⁺ or [Tc^(V) O_(2]) ⁻ respectively.¹,2 Technetium (V) oxo-species are used to image kidney, liver, brain and bone tissues.

The terminal imido (2-) moiety, ═NR, is formally isoelectronic to a terminal oxo (2-) function,=0. Many transition metal complexes containing an organo-imido ligand are known³. Examples include the following complexes based on rhenium⁴,5,6, (I, II), tungsten⁷ (III), vanadium⁸ (IV) and molybdenum⁹ (V): ##STR1## where Ar is an aryl group.

When the R substituent of a terminal imide ligand is a dialkyl amide moiety, NY₂, the imide ligand is more often described as a hydrazide (2-) ligand. Thus the terminal hydrazido (2-) moiety, ═N--NR₂, is also isoelectronic to a terminal oxo (2-) function, and many transition metal complexes containing hydrazido (2-) ligands are known¹⁰. Examples of isostructural metal-oxo and metal-hydrazido (2-) complexes include the following ¹¹,12,13,14 : ##STR2##

Similarly, the diazenido moiety, --N═NR, is isoelectronic and isostructural with the nitrosyl ligand (--NO).

Unlike oxo- and nitrosyl ligands, however, imide (2-), hydrazido (2-) and diazenido ligands can carry a variety of different substitutents on the nitrogen atom which is not bound to the metal atom. The presence of any of these three moieties in a technetium complex therefore permits the preparation of new radiopharmaceuticals with a variety of biological characteristics which can be modulated by varying or altering the R substituents. In addition, the methods for the synthesis of complexes containing Tc═NR, Tc═N--NY₂ or Tc--N═NY moieties are compatible with the concomitant ligation of a wide variety of other ligands. It is this discovery which forms the basis of the present invention.

According to this invention there is provided a complex of technetium (⁹⁹ Tc or ^(99m) Tc) which contains the moiety Tc═NR, Tc--N═NY or Tc(--N═NY)₂, and a ligand which confers biological target-seeking properties on the complex,

wherein R represents an aryl group, a substituted or unsubstituted alkyl group, or the grouping NR¹ R² ;

Y represents an aryl group or a substituted or unsubstituted alkyl group;

and

R¹ and R² are hydrogen, aryl groups or substituted or unsubstituted aliphatic or cyclic alkyl groups, and may be both the same or different, provided that both are not hydrogen.

The complex is useful as a radiopharmaceutical.

Complexes in accordance with this invention have the formulae:

    L.sub.n Tc═NR; L.sub.n Tc--N═NY or L.sub.n Tc(--N═NY).sub.2

wherein L represents a mono- or multi-dentate ligand;

n is 1, 2, 3 or 4.

and

R and Y are as defined above.

The alkyl group substituents may be aliphatic (straight chain or branched) or cyclic, and may be substituted with, for example, oxygen, nitrogen, sulphur and/or phosphorus.

A wide range of ligands for these complexes are envisaged, including:

a) Phosphines and arsines of the general formula Q₂ B(CD₂)_(n) BQ₂, where B is P or As; Q is H or aryl or substituted or unsubstituted alkyl, preferably C1-C4 alkyl or phenyl; n is 1, 2, 3 or 4; and (CD₂) is a substituted or unsubstituted methylene group. Related compounds are described in:--U.S. Pat. No. 4,481,184, U.S. Pat. No. 4,387,087, U.S. Pat. No. 4,489,054, U.S. Pat. No. 4,374,821, U.S. Pat. No. 4,451,450, U.S. Pat. No. 4,526,776, EP-A-0266910 (Amersham International; methylene bridged diphosphine complexes), EP-A-0311352 (Amersham International; phosphines containing ether groups), and ligands of general type

    R.sup.3.sub.m B--(CH.sub.2).sub.n --W--(CH.sub.2).sub.n --W--(CH.sub.2).sub.n --BR.sup.3.sub.m

where B is P or As,

W is NR, S, Se, O, P or As,

R³ is H or hydrocarbon such as C1-C6 alkyl or aryl,

m is 1 or 2, and

n is 1, 2, 3 or 4.

b) Methylene Diphosphonate (MDP)

c) Thiourea (TU)

d) Thiomalate (TMA)

e) Dimercaptosuccinic acid (DMSA)

f) Gluconate (GLUC)

g) Ethane-1-hydroxy-1,1-diphosphonate (EHDP)

h) Diethylene triamine pentaacetic acid (DTPA)

i) N-(2,6-[Dialkyl]phenyl carbamoylmethyl) iminodiacetate

alkyl=Methyl (HIDA)

Ethyl (EHIDA)

^(i) Propyl (PIPIDA)

j) Dialkyl dithiocarbamate

k) Isonitriles of the general type C═NR⁴

R⁴ =alkyl, alkoxy, ether

l) BAT Derivatives--of the general type illustrated below, and specifically:

i) R⁵ =R¹¹ =H

R⁶,7,9,10 =Et

R⁸ =N-methylspiropiperidinyl

ii) R⁵ =R¹¹ =H

R⁶,7,9,10 =Et

R⁸ =N-ethylspiropiperidinyl

iii) R⁵ =R¹¹ =H

R⁶,7,9,10 =Et

R⁸ =N-isopropylspiropiperidinyl ##STR3## m) phenanthroline, n) pentane-2,4-dione,

o) bipyridyl,

p) Other ligands having propylene amine oxime backbone of the general structural types described in EPA 123504 and 194843: ##STR4## q) Bisthiosemicarbazones of the formula: ##STR5## where the various groups R¹² can be the same or different and are H and/or alkyl and/or aryl substituents. Other suitable ligands are shown in Table 1.

The invention further provides methods for the preparation of the aforementioned complexes of technetium. One such method involves the derivatisation of technetium oxo-containing species by condensation with hydrazines or amines (equation A), isocyanates (equation B), sulphinylamines (equation C) or phosphinimines (equation D):

A: L_(n) Tc═O+H₂ NR→L_(n) Tc═NR+H₂ O

B: L_(n) Tc═O+OCNR→L_(n) Tc═NR+CO₂

C: L_(n) Tc═O+OSNR→L_(n) Tc═NR+SO₂

D: L_(n) Tc═O+Ph₃ P═NR→L_(n) Tc═NR+Ph₃ P═O

wherein R, L and n are defined as above.

The driving force for these reactions is the formation of a stable product containing the former oxo function (i.e. water, carbon dioxide, sulphur dioxide or phosphine oxide), which is generally easily removed after the oxo group transfer, leaving the desired technetium hydrazido (2-) or imido complex.

An alternative method of preparation involves the reaction of hydrazines (equation E) or amines (either aliphatic or aromatic) (equation F) with complexes containing technetium-halogen bonds:

E: L_(n) Tc Cl₂ +H₂ NNR¹ R² →L_(n) Tc═NNR¹ R² +2HCl

F: L_(n) Tc Cl₂ +H₂ NR→L_(n) Tc═NR+2HCl

where L, R, R¹ and R² are as previously defined.

The driving force for these reactions is the concomitant formation of the volatile, easily removed hydrogen halide during the metathesis reaction.

It will be appreciated that the hydrazides and diazenides can be considered as essentially being functionalised imide ligands. The hydrazide (2-) ligand, ═NNR¹ R², is just the imide ligand, ═NR, where R is NR¹ R² ; and the diazenide ligand results when R₁ is hydrogen. In this case, the intermediate hydrazide (2-) complex is deprotonated by a base to give a metal-diazenide complex with concomitant reduction of the metal centre: ##STR6## In the reaction reported herein, the base is always the added excess of hydrazine in the solution.

Turning now to the preparation of the technetium complexes containing an imido moiety, the approach has been to replace the oxo function in [TcOX₄ ]⁻ (X═Cl, Br) using arylisocyanates (reaction type equation B). This formed a convenient entry point into the work by extending an established route for the synthesis of Tc═NR complexes. This method has only been previously used for generation of neutral imido products from neutral transition metal oxo starting materials.¹⁷ The work reported here is thus the first example of the method extended to the preparation of anionic transition metal imido complexes, and also to technetium chemistry.

Reaction of [Tc^(V) OX₄ ]⁻ with excess ArNCO in refluxing dry toluene under nitrogen gives excellent yields of the desired Tc^(V) -imido products isolated as solids on ether trituration of the residue obtained directly from the reaction mixture (equation G): ##STR7##

Even though the method gives good yields of reasonably pure solids, the reaction is not trivial. The starting isocyanates are quite moisture and air sensitive such that the reaction must be strictly performed under an atmosphere of N₂. 1 and 2 are black-blue solids that are also quite sensitive to adventitious moisture, however, they are stable under dry N₂. That the products are very sensitive to moisture is evidenced by the fact that if reagent grade diethyl ether is used in the trituration phase of the workup procedure instead of anhydrous ether, then the product is isolated as a red-brown insoluble polymeric compound. The products also do not always chromatograph (HPLC) satisfactorily.

The products [Tc(Ntol)X₄ ]⁻ contain the new core moiety [Tc^(V) ═NR]³⁺ which is formally analogous to the well known [Tc═O]³⁺ core¹. [Tc(NR)X₄ ]⁻ is a sixteen electron species in which the imido ligand functions as a four electron donor; the technetium-nitrogen bond is therefore expected to be a short, linear multiple [Tc═NR] bond. Attempted structural characterisation of [Tc(Ntol)Cl₄ ]⁻ as its PPh₄ ⁺ salt by X-ray crystallography has so far been unsuccessful due to its sensitive nature. The products 1 and 2 are very good starting materials for the preparation of many new Tc═NR complexes.

In view of the somewhat sensitive nature of 1 and 2, investigation of much more stable Tc-imido complexes was undertaken. The direct metathesis reactions of [TcOCl₄ ]⁻ with aromatic amines was undertaken in the presence of phosphine ligands. Reactions of this type may show promise in ^(99m) Tc chemistry in view of the wide variety of substituted aromatic amines available commercially.

Reaction of [TcOCl₄ ]⁻ with ArNH₂ in refluxing MeOH in the presence of the monodentate phosphine PPh₃ gives the green-brown neutral Tc^(V) imido complexes which analyse for [Tc(NR)Cl₃ (PPh₃)₂ ] (equation H): ##STR8##

Chromatographic analysis (HPLC, beta detection) of these products show only one significant ⁹⁹ Tc-containing species. These neutral Tc^(V) complexes also contain the new [Tc^(V) ═NR]³⁺ core. They are diamagnetic, air-stable solids which are very soluble in CH₂ Cl₂, CHCl₃, moderately soluble in alcohols, and insoluble in ether and petrol. They exhibit a singlet (ca. 30 ppm) in the ³¹ P NMR spectrum, indicating two trans-PPh₃ groups in identical environments. Structural characterisation of 3 by X-ray has now been carried out and FIG. 1 gives a Ball and Stick representation of the complex molecule. The diagram shows a linear tolylimide group and the two PPh₃ groups to be trans. The [Tc═Ntol] unit in 3 may therefore be correctly assigned as a linear four electron donor imido ligand, and the complex is formally an 18-electron species.

This work therefore represents the first structurally characterised Tc^(V) -imido complex.

The [Tc(NR)Cl₃ (PPh₃)₂ ] compounds are much superior starting materials than [Tc(NR)X₄ ]⁻ because these are much more stable Tc═NR species.

Reaction of [TcOCl₄ ]⁻ with excess amine and dppe in refluxing MeOH or EtOH allows the isolation of good yields of the cationic Tc-imido complexes [Tc^(IV) (NC₆ H₄ Z)Cl--(dppe)₂ ]⁺ as their BPh₄ ⁻ salts (equation I): ##STR9##

These complexes 6,7 and 8 are all air-stable darkly coloured cationic Tc^(IV) -imido complexes. Chromatographic analysis (HPLC, beta detection) indicates single ⁹⁹ Tc-containing species. They are quite soluble in CH₂ Cl₂ and insoluble in ether, petrol and alcohols. They may be conveniently recrystallised from CH₂ Cl₂ /MeOH.

Their assignment as Tc(IV) complexes is from the following characterization: The analysis stoichiometry fits the formula [Tc(NR)Cl(dppe)₂ ](BPh₄). Although νTc═N is not assignable there is no evidence for νNH in the infrared. The compounds exhibit very broadened NMR spectra (¹ H, ³¹ P) at room temperature which are not easily assigned. They are assumed to be paramagnetic Tc^(IV) imido complexes and not Tc^(III) -amido (TcNHR) complexes on this basis.

This represents another new core, the [Tc^(IV) ═NR]²⁺ moiety. Evidence for the existence of this new Tc^(IV) core comes from the structural characterisation of a [Tc^(IV) -hydrazido(2-)bis(dppe)Cl]⁺ cation which contains a [Tc^(IV) NNR₂ ]⁺ core¹⁸. Hydrazido(2-) and imido(2-) are formally analogous. Further evidence comes from the existence and relative stability of the analogous [Tc^(IV) ═O]²⁺ core from the electrochemical reduction of some Tc^(V) oxo Schiff base complexes¹⁹.

It is to be understood that reactions of the aforementioned type A-F are well known for the synthesis of various transition metal hydrazido (2-) and imido complexes ³,10. While it is believed that they have not previously been used for the production of technetium complexes of the kind described and claimed herein, it is acknowledged that the synthesis of technetium-nitride complexes using hydrazine hydrochloride itself has already been reported ¹⁵,16.

Using the approach of equation A above, the reactions of hydrazines with [NBu₄ ] [TcOCl₄ ] were studied, and the intermediate products further functionalised with mono- or bi-dentate ligands. In particular, the reaction of complexes containing technetium-oxo moieties [Tc═O] with mono-substituted hydrazines or 1,1-disubstituted hydrazines produces technetium-diazenide or technetium-hydrazide (2-) species.

The facile synthesis of [TcCl(NNPh)₂ (PPh₃)₂ ] from [Bu₄ N][TcOCl₄ ], PhNHNH₂, and PPh₃ in methanol under reflux has been demonstrated.²⁵ This complex proved to be somewhat insoluble and could not be satisfactorily recrystallised due to its poor solubility. This unsubstituted phenyl-diazenido-complex thus appears to be polymeric, possibly containing chloro-bridges. Consequently it was not thought to be a suitable starting material for investigation of substitution chemistry.

Use of 4-substituted hydrazine hydrochlorides 4--XC₆ H₄ NHNH₂.HCl (X═Cl, CH₃) has lead to the preparation of the analogous bisdiazenido-complexes [TcCl (NNC₆ H₄ X)₂ (PPh₃)₂ ] (X═Cl, 9; X═CH₃, 10). These air-stable orange crystalline solids are reasonably soluble compounds and are much superior starting materials. Complex 9 (X═Cl) in particular has proved to be the most suitable for a systematic investigation of the substitution chemistry of the technetium bis diazenido-complexes, giving relatively clean products on reaction with the appropriate ligand.

A most important development in this work is the fact that these diazenido-complexes [TcCl(NNR)₂ (PPh₃)₂ ] may also be synthesised directly from [TcO₄ ]⁻. Reaction of [NH₄ ] [TcO₄ ] with ClC₆ H₄ NHNH₂.HCl and PPh₃ in dry methanol under reflux gives a good (60-70%) yield of [TcCl(NNC₆ H₄ Cl)₂ (PPh₃)₂ ] 9. Many variations in experimental conditions were tried. The best method is reported here. This result suggests that all technetium diazenido-complexes may be synthesised in good yield directly from [TcO₄ ]⁻.

In order to investigate which complexes could be synthesised directly from [TcO₄ ]⁻ in future work, it has been important to demonstrate that the diazenido- (and imido-) cores may be incorporated into a wide variety of complex types. For diazenido-cores this has mainly been approached by the systematic substitution of 9.

Reaction of 9 with excess dppe in methanol under reflux gives pure [TcCl(NNC₆ H₄ Cl)(dppe)₂ ]⁺, 12 isolated as orange crystalline BPh₄ ⁻ or PF₆ ⁻ salts in good yield. Complexes of this type may also be prepared directly from [NH₄ ][TcO₄ ].

Reaction of 9 with dmpe under similar conditions leads to the isolation of a pale-pink cationic solid (HPLC retention time 10 minutes, single species) containing no nitrogen. This product could not be isolated in pure form, but is tentatively formulated as [Tc^(I) (dmpe)₃ ][BPh₄ ]. The analogous reaction under less forcing conditions at room temperature leads to the desired cation [TcCl(NNC₆ H₄ Cl)(dmpe)₂ ]⁺ isolated as its PF₆ ⁻ salt (HPLC retention time 9.6 minutes, single species).

In order to elucidate the validity of both [Tc(N₂ Ar)₂ ⁺ and [Tc(N₂ Ar)]²⁺ as new cores for the development of Tc-based radiopharmaceutical products it was necessary to investigate the lability of the --N₂ Ar unit on reaction with other ligands. Detailed HPLC experiments (beta detection) were performed to see if a bis diazenido-intermediate was formed in the preparation of the cation 12 (retention time 14 minutes) from the starting material 9 (retention time 9.4 minutes). The HPLC results showed that the cation formed after only 15 minutes stirring at room temperature, and that no other Tc-containing intermediate was detected. This proves that one --N₂ Ar moiety is very labile, and is easily lost in solution at room temperature in the presence of the appropriate ligand to give the monodiazenido-product.

Reaction of 9 and 10 with the less bulky phosphines (PMe₂ Ph, PMePh₂) gave single species in solution (HPLC). However, the high solubility precluded further workup of these apparently cationic products. Reaction of [Bu₄ N] [TcOCl₄, XC₆ H₄ NHNH₂.HCl (X═Cl, CH₃) and the appropriate phosphine also leads to isolation of these solutions (HPLC).

Reaction of the commercially available hydrazine O₂ NC₆ H₄ NHNH₂ with [Bu₄ N] [TcOCl₄ ] and PPh₃ in methanol leads to the isolation of the lime-green Tc(lII) monodiazenido-complex [TcCl₂ (NNC₆ H₄ NO₂)(PPh₃)₂ ], 11 in reasonable yield. Apparently a bis diazenido-complex is not formed from reaction of this nitro-substituted phenylhydrazine. The complex 11 promises to be a useful starting material for the preparation of a variety of monodiazenido-complexes as it has two easily replaceable chlorides. In the presence of dppe in methanol-toluene under reflux complex 11 gives orange [TcCl(NNC₆ H₄ NO₂)(dppe)₂ ]⁺, 13 isolated as its BPh₄ ⁻ salt in good yield. [TcCl(NNC₆ H₄ NO₂)(dmpe)₂ ][PF₆ ] (retention time 10 minutes, single species) was prepared in high yield directly from [TcOCl₄ ]⁻, the hydrazine, and dmpe in refluxing methanol-toluene.

Reaction of 9 with sodium dimethyidithio-carbamate in absolute ethanol under reflux gives the novel orange Tc(III) diazenido-complex [Tc(NNC₆ H₄ Cl) (S₂ CNMe₂)₂ (PPh₃)], 14 in reasonable (66%) yield. Complex 14 is air-stable both in the solid state and in solution. Recrystallisation from CH₂ Cl₂ /Et₂ O gives X-ray quality orange crystals. Satisfactory elemental analysis and spectroscopic data suggest the formulation to be correct. The room temperature ¹ H NMR spectrum of 14 is indicative of its coordination geometry. The four methyl groups in 14 appear as four sharp singlets. This resonance pattern shows that the two dithiocarbamato ligands are non-equivalent, and is consistent with a cis-conformation. This has to be confirmed by X-ray structure analysis. If the dithiocarbamato ligands were trans- and the four methyl groups thus equivalent, the ¹ H spectrum would show a single resonance which would not be expected to change with temperature.

Reaction of 9 with maltol gives a dark-orange crystalline compound. This is a single species (HPLC) and analyses as [TcCl(NNC₆ H₄ Cl)(maltol) (PPh₃)₂ ], 15. This novel Tc(III) diazenido complex is formally analogous to the structurally characterised [ReCl(NNCOPh)(maltol)(PPh)₃)₂ ]²⁶, and is the first reported Tc complex containing the maltol ligand.

Reaction of 9 with the tetradentate N₂ O₂ (2-) ligand salenH₂ in methanol-toluene under reflux in the presence of Et₃ N gives the neutral dark-green Tc(III) diazenido-complex [Tc(NNC₆ H₄ Cl)(salen)(PPh₃)], 16 in good yield. Similar reaction of 9 with the obligately planar tetradentate N₂ O₂ (2-) ligand salphenH₂ gave no well defined product suggesting that a cis-geometry of the --N₂ Ar and PPh₃ groups is preferred. Further evidence for a preferred cis-geometry is suggested from the spectroscopic results of 14. This is expected to be confirmed by X-ray structure analysis.

Reaction of 9 with the N₂ S₂ ligand (HSCH(Me)CONHCH₂ -)₂ in the presence of Et₃ N gave a dark-brown solid. The product was too insoluble for satisfactory analysis by NMR, but appeared to be diamagnetic. Elemental analysis on the product isolated directly from the reaction mixture suggested the formulation as a bis diazenido-complex [Tc(NNC₆ H₄ Cl)₂₋ (SCH(Me)CONHCH₂ CH₂ NHCOCH(Me)S)]_(x), 17.

Much effort has been directed to the development of a synthetic route to Tc imido-complexes directly from [TcO₄ ]⁻. Reaction of aqueous methanolic solutions of [TcO₄ ]⁻ with aromatic amine and PPh₃ in the presence of concentrated HCl gives only low yields of the desired Tc(V) imido-complexes [(TcCl₃ (NAr)(PPh₃)₂ ]. These complexes have been prepared previously from [Bu₄ N][TcOCl₄ ].²⁵ The nature of the reaction from [TcO₄ ]⁻ appears to be very dependent on the concentration of HCl used. Use of excess HCl gives [TcCl₄ (PPh₃)₂ ].

The use of amine hydrochloride (ArNH₃ Cl) as an alternative to the addition of HCl in this reaction has also been investigated in some detail. [TcO₄ ]⁻ reacts with ArNH₃ Cl and PPh₃ in aqueous methanol to give a bright blue, neutral product in high yield after about 20 minutes stirring at room temperature. This product appears to be independent of the aromatic amine hydrochloride used. The blue compound appears to be diamagnetic (NMR) and shows evidence for coordinated PPh₃ but contains no nitrogen. This compound analyses reasonably as [Tc₂ Cl₄ (PPh₃)₄ ] which is analogous to many known Re--Re multiply bonded species. Use of aliphatic amine hydrochlorides (RNH₃ Cl) leads to rapid conversion to black insoluble "TcO₂.xH₂ O".

Reaction of [NH₄ ][TcO₄ ] with the hydrochloride of anthranilic acid (2--HO₂ CC₆ H₄ NH₃ Cl) under analogous conditions gives a lime-green precipitate. This analyses reasonably well as [TcCl₂ (NC₆ H₄ CO₂)(PPh₃)₂ ], 18 and is expected to have the novel structure containing a bent TcNC framework. The bent chelating imidobenzoate(3-) ligand is thus a new core moiety for technetium. The complex 18 may also be prepared from [TcOCl₄ ]⁻ in lower yield. Anthranilic acid is known to react with [ReOCl₃ (PPh₃)₂ ] in ethanol to give the chelating imidobenzoate(3-) complex [ReCl(OEt)(NC₆ H₄ CO₂)(PPh₃)₂ ].²⁷ ##STR10##

This is a major development as it suggests that imido-complexes are more generally accessible from [TcO₄ ]⁻. The chelate effect must in some way stabilise the formation of this imido-ligand. The establishment of a conjugation pathway through the M═N, C═C, and C═O may be a driving force for its formation. The reaction of [TcO₄ ]⁻ and anthranilic acid hydrochoride in the presence of a wide variety of non-phosphine ligands is envisaged.

Much effort has been directed to synthesis of Tc imido-ligands from [TcO₄ ]⁻ using the hydrazines RCONHNHAr (R═CH₃, Ph), and also their hydrochlorides as a source of the NAr ligand. Use of the symmetrically substituted hydrazines RNHHNR (R═Me, Et, PhCO, Ph) is also envisaged. Preliminary experiments for both [Tco₄ ]⁻ and [TcOCl₄ ]⁻ have shown that mixtures of products are being formed (HPLC).

Our work has resulted in the synthesis of two new classes of technetium complexes with hydrazido (2-), i.e. .sup.═ NNR₂, and diazenido, i.e. --NNR, substituents, at both the carrier added (⁹⁹ Tc) and the no carrier added (^(99m) Tc) levels. Both neutral and cationic derivatives have been prepared within each class. These complexes are useful as radiopharmaceuticals and thus provide a new range of such reagents.

Specifically, the following new complexes containing hydrazido (2-) and diazenido moieties have been prepared:

⁹⁹ Tc: Carrier Added Level

[Tc^(V) (NNMePh)Cl₃ (PPh₃)₂ ]

[Tc^(V) (NNMePh)Cl₂ (PMe₂ Ph)₃ ][PF₆ ]

[Tc^(V) (NNMePh)Cl(Et₂ NCS₂)₂ ]

[Tc(N₂)Cl(dppe)₂ ]

[Tc^(IV) (NNMe₂)Cl(dppe)₂ ][PF₆ ]

[Tc^(V) O(NH)dppe][PF₆ ]

[Tc^(III) (NNPh)₂ Cl(PPh₃)₂ ]

[Tc^(III) (NNPh)Cl(dppe)₂ ][PF₆ ]

[Tc(NNC₆ H₄ Cl)Cl(dppe)₂)[PF₆ ]

[Bu₄ N][Tc(NC₆ H₄ CH₃)Br₄ ], [Bu₄ N][Tc(NC₆ H₄ CH₃)Cl₄ ], Tc

(NC₆ H₄ Z)Cl₃ (PPh₃)₂ where Z═CH₃, Br, Cl,

[Tc(NC₆ H₄ Z)Cl(dppe)₂ ][BPh₄ ], where Z is as above.

^(99m) Tc: No-Carrier Added Level*

[Tc^(III) (NNPh)Cl(L)₂ ]⁺

L=dmpe, dppe, P46, P53, P56, P68, PL28, PL31, PL34, PL37, PL38, PL40, PL42, PL43, PL46, PL49, PL50.

[Tc^(III) (NNC₆ H₄ NO₂)Cl(L)₂ ]⁺

L=dmpe

[Tc^(IV) (NNMePh)Cl(L)₂ ]⁺

L=dmpe, P34, P46, P53, P65, P68, PL28, PL38

Of these, animal biodistribution data has been obtained for the following ^(99m) Tc species and the results are shown in Tables 2, 3 and 4:

[Tc^(III) (NNPh)Cl(L)₂ ]⁺

L=dmpe, PL28, P46, PL42, PL43, P65, PL50, PL38 (Table 2)

[Tc^(III) (NNC₆ H₄ NO₂)Cl(L)₂ ]⁺

L=dmpe (Table 3)

(Tc^(IV) (NNMePh)Cl(L)₂ ]⁺

L=dmpe, P46, P65 (Table 4)

This invention will now be further illustrated by the following Examples:

⁹⁹ Tc Complexes

All reactions were performed under an atmosphere of nitrogen using predried, distilled solvents unless noted otherwise. [NBu ₄ ] [TcOCl] was prepared by the literature procedure²⁰. All other reagents used were obtained from commercial sources and used as received. Aqueous solutions of [NH₄ ][TcO₄ ] were obtained from Amersham International plc.

All complexes were characterised by elemental analysis, IR, ¹ H NMR and ³¹ P NMR. Only analytical data are included here but spectroscopic information is available. In addition to the above physical characterisation of the complexes single crystal X-ray structures have been obtained for four complexes:

[Tc(NNPh)Cl(dppe)₂ ][PF₆ ], [Tc(NH)O(dppe)₂ ][PF₆ ],

[Tc(NNMe₂)Cl(dppe)₂ ][PF₆ ] and Tc(NC₆ H₄ CH₃)Cl₃ (PPh₃)₂.

EXAMPLE 1

Reaction of (Bu₄ N)[TcOX₄ ] (X═Cl, Br) with 4-Tolyl-isocyanate

i) Tetrabutylammonium(1+)tetrachloro(p-tolylimido) technetate (V) (1-), (Bu₄ N)[Tc(Ntol)Cl₄ ]1

(Bu₄ N)[TcOCl₄ ] (0.194 g, 0.39 mmol) was suspended in dry degassed toluene (10 ml) and MePhNCO (0.25 ml, 1.98 mmol, 5 equivalents) was added. The mixture was then vigorously refluxed under N₂ for 45 minutes. After cooling to room temperature the toluene was decanted off, and the black residue was triturated with dry diethyl ether (10 ml) before collection of the blue-black solid 1 by filtration. On washing thoroughly with diethyl ether the product was dried in vacuo. (Yield 0.229 g, 0.39 mmol, 100%). In similar preparations of 1 the yield was never less than 95% and therefore the conversion was considered to be essentially quantitative. (Found: C, 49.31; H, 7.22; N, 5.02. calc for TcC₂₃ H₄₃ N₂ Cl₄ : C, 47.03; H, 7.37; N, 4.77%); ¹ H NMR (d₆ -DMSO) 0.9[12H, broad unresolved triplet, (CH₃ (CH₂)₃)₄ N]; 1.4[24H, broad multiplet, (CH₃ (CH₂)₃)₄ N]; 2.2[3H, singlet, CH₃ C₆ H₄ N--Tc]; 7.0-7.4[4H, multiplet, CH₃ C₆ H₄ NTc]; v_(max). (Nujol mull, KBr plates) 1170 m br cm⁻¹ (Tc═N, tentative assignment).

ii) Tetrabutylammonium(1+)tetrabromo(p-tolylimido) technetate (V) (1-), (Bu₄ N)[Tc(Ntol)Br₄ ] 2

The blue-black product 2 was prepared in a similar fashion to 1 using (Bu₄ N)[TcOBr₄ ] (0.268 g, 0.396 mmol) and MePhNCO (0.25 ml, 1.98 mmol, 5 equivalents) in refluxing dry toluene (15 ml). (Yield 0.224 g, 0.29 mmol, 74%). HPLC retention time 9.6 minutes, single species; (Found: C, 36.73; H, 6.43; N, 3.16. calc for TcC₂₃ H₄₃ N₂ Br₄ : C, 36.10; H, 5.66; N, 3.66%); ¹ H NMR (CDCl₃) 1.0[12H, broad unresolved triplet, (CH₃ (CH₂)₃)₄ N]; 1.5[24H, broad multiplet, (CH₃ (CH₂)₃)₄ N]; 2.27[3H, singlet, CH₃ C₆ H₄ NTc]; 6.9-7.5[4H, multiplet, CH₃ C₆ H₄ NTc]; v_(max). (Nujol mull, KBr plates) 1175 cm⁻¹ (Tc═N, tentative assignment).

EXAMPLE 2

Reactions of (Bu₄ N)[TcOCl₄ ] with Aromatic Amines (4-ZC₆ H₄ NH₂, Z═CH₃, Br, Cl) in the Presence of Triphenylphosphine, PPh₃

i) Trichloro(p-tolylimido)bis(triphenylphosphine) technetium (V), Tc(NC₆ H₄ Z)Cl₃ (PPh₃)₂ Z=CH₃, 3

(Bu₄ N)[TcOCl₄ ] (0.216 g, 0.43 mmol), CH₃ C₆ H₄ NH₂ (0.07 g, 0.65 mmol, 1.5 equivalents) and PPh₃ (0.34 g, 1.3 mmol, 3 equivalents) were refluxed in dry methanol (10 ml) under N₂ for 40 minutes. After cooling to room temperature, the brown-green mixture was evaporated to 5 ml, and diethyl ether (15 ml) was added to aid precipitation of 3. The green-brown product was collected by filtration, washed thoroughly with ether and dried. The product could be recrystallised from CH₂ Cl₂ /hexane mixture. (Yield 0.094 g, 0.11 mmol, 26%). HPLC retention time 10.8 minutes, single species; (Found: C, 59.01; H, 4.35; N, 1.76; Cl, 12.80. calc for TcC₄₃ H₃₇ NCl₃ P₂ : C, 61.84; H, 4.46; N, 1.68; Cl, 12.74%); ¹ H NMR (CDCl₃) 2.2[3H, s, CH₃ C₆ H₄ NTc]; 6.5-6.8[4H, m, CH₃ C₆ H₄ NTc]; 7.0-8.0[30H, m, phenyl H]. There was no evidence of NH in the proton spectrum; ³¹ P--{¹ H} NMR (CDCl₃) 30.02 s ppm; v_(max) (Nujol mull, KBr plates) 1165 cm⁻¹ (Tc═N, tentative assignment). There were no absorptions which could be attributed to ^(V) NH.

ii) Trichloro(p-bromophenylimido)bis(triphenylphosphine) technetium (V), Tc(NC₆ H₄ Z)Cl₃ (PPh₃)₂ Z═Br, 4

(Bu₄ N) (TcOCl₄ ] (0.210 g, 0.42 mmol), BrC₆ H₄ NH₂ (0.11 g, 0.64 mmol, 1.5 equivalents) and PPh₃ (0.331 g, 1.26 mmol, 3 equivalents) were refluxed in dry methanol (10 ml) to give on workup and recrystallisation from CH₂ Cl₂ /hexane a very low yield of brown solid 4. (Yield 0.052 g, 0.06 mmol, 14%). HPLC retention time 9.6 minutes, single species; (Found: C, 54.38; H, 4.00; N, 1.53; Cl, 10.56. calc for TcC₄₂ H₃₄ NP₂ Cl₃ Br: C, 56.05; H, 3.81; H, 1.56; Cl, 11.82. calc for TcC₄₂ H₃₄ NP₂ C₃ Br.1/2 CH₂ C₂ : C, 54.45; H, 3.72; N, 1.48; Cl, 14.95%); ¹ H NMR (CDCl₃) 5.25[s, CH₂ Cl₂ ]; 6.8[4H, m, BrC₆ H₄ NTc]; 7.0-8.0[30H, m, phenyl H]; ³¹ P--{¹ H} NMR (CDCl₃) 29.93 s ppm; v_(max). (Nujol mull, KBr plates) 1165 cm⁻¹ (Tc═N, tentative assignment).

iii) Trichloro(p-chlorophenylimido)bis(triphenylphosphine) technetium (V), Tc(NC₆ H₄ Z)Cl₃ (PPh₃)₂ Z═Cl, 5

(Bu₄ N)[TcOCl₄ ] (0.272 g, 0.545 mmol), ClC₆ H₄ NH₂ (0.104 g, 0.82 mmol, 1.5 equivalents) and PPh₃ (0.43 g, 1.64 mmol, 3 equivalents) were refluxed in dry methanol (10 ml) to give a very low yield of brown solid 5. (Yield 0.084 g, 0.098 mmol, 18%). HPLC retention time 9.2 minutes, single species; (Found: C, 55.85; H, 3.86; N, 1.63. calc for TcC₄₂ H₃₄ NP₂ Cl₄ : C, 58.96; H, 4.00; N, 1.64%); ¹ H NMR (CDCl₃)6.5-6.7[4H, m, ClC₆ H₄ NTc]; 7.0-8.0[30H, m, phenyl H]; ⁻ P--(¹ H) NMR (CDCl₃) 29.87 s ppm; v_(max). (Nujol mull, KBr plates) 1170 cm⁻¹ (Tc═N, tentative assignment.

EXAMPLE 3

Reactions of (Bu₄ N)[TcOCl₄ ] with Aromatic Amines (4-ZC₆ H₄ NH₂, Z═CH₃, Br, Cl) in the Presence of Bis(diphenylphosphino)ethane, dppe

i) [Tc(NC₆ H₄ Z)Cl(dppe)₂ ](BPh₄) Z═CH₃, 6

(Bu₄ N)[TcOCl₄ ] (0.333 g, 0.67 mmol), CH₃ C₆ H₄ NH₂ (0.36 g, 3.33 mmol, 5 equivalents), and dppe (0.80 g, 2.0 mmol, 3 equivalents) in dry degassed methanol (20 ml) were refluxed for 1 hour. After cooling to room temperature, the violet mixture was filtered into a clean flask to remove some insoluble red material. Sodium tetraphenylborate (0.23 g, 0.67 mmol) in methanol (5 ml) was added with stirring to immediately precipitate out a copious amount of violet solid 6. The product was collected by filtration and washed thoroughly with MeOH, and then ether. The product could be recrystallised from CH₂ Cl₂ /MeOH or CH₂ Cl₂ /hexane. (Yield 0.544 g, 0.40 mmol, 60%). HPLC retention time 8.4 minutes, one major species; (Found: C, 74.09; H, 7.09; N, 1.70; Cl, 3.22. calc for TcC₈₃ H₇₅ NClP₄ B: C, 73.54; H, 5.58; N, 1.03; Cl, 2.62%).

There are no infrared absorptions assignable to NH stretches, and the ^(V) Tc═N stretch could not be assigned unambiguously. The product gave a broadened ¹ H NMR spectrum and was assumed to be paramagnetic Tc(IV). The ⁻ P NMR spectrum also showed broadened resonances.

If less ArNH₂ was used in the reaction a red precipitate believed to be [Tc^(III) Cl₂ (dppe)₂ ]Cl forms in approximately 50% yield from the MeOH on cooling to room temperature.

ii) [Tc(NC₆ H₄ Z)Cl(dppe)₂ ](BPh₄) Z═Br, 7

(Bu₄ N)[TcOCl₄ ] (0.179 g, 0.36 mmol), BrC₆ H₄ NH₂ (0.31 g, 1.79 mmol, 5 equivalents) and dppe (0.429 g, 1.08 mmol, 3 equivalents) were refluxed in dry methanol (10 ml, 1 hour). NaBPh₄ (0.122 g, 0.36 mmol) in MeOH (5 ml) was added to the cooled filtered reaction mixture with stirring to isolate 7 as a maroon solid on filtration. (Yield 0.325 g, 0.23 mmol, 64%). HPLC retention time 7.6 minutes, one major species. Analysis on the crude material gave (Found: C, 73.19; H, 5.91; N, 0.89; Cl, 3.19. calc for TcC₈₂ H₇₂ NBrClP₄ B: C, 69.33; H, 5.11; N, 0.99; Cl, 2.50%) and suggests contamination with BPh₄ ⁻ or Cl⁻. The product could be recrystallised from CH₂ Cl₂ /MeOH.

iii) [Tc(NC₆ H₄ Z)Cl(dppe)₂ ](BPh₄) Z═Cl, 8

(Bu₄ N)[TcOCl₄ ] (0.28 g, 0.56 mmol), ClC₆ H₄ NH₂ (0.358 g, 2.8 mmol, 5 equivalents) and dppe (0.67 g, 1.68 mmol, 3 equivalents) were refluxed in dry methanol (15 ml, 75 minutes). NaBPh₄ (0.19 g, 0.56 mmol) in MeOH (5 ml) was added to the cooled filtered reaction mixture with stirring to precipitate out the dark maroon solid 8 which was collected by filtration. (Yield 0.497 g, 0.36 mmol, 64%). HPLC retention time 8.0 minutes, one major species. Analysis on the crude material gave (Found: C, 73.56; H, 5.94; N, 1.72; Cl, 3.26. calc for TcC₈₂ H₇₂ NCl₂ P₄ B: C, 71.57; H, 5.27; N, 1.02; Cl, 5.15%) and suggests contamination with BPh₄ ⁻. The product could be recrystallised from CH₂ Cl₂ /MeOH.

EXAMPLE 4

The preparation of [Tc(NNPh)₂ Cl(PPh₃)₂ ]

Dry, distilled MeOH (5 cm³) was added to a reaction flask containing a magnetic stirring bar, 222 mg PPh₃ (0.85 mmol) and 70 mg [NBu₄ ][TcOCl₄ ] (0.14 mmol). This gave an orange suspension containing undissolved PPh₃. After five minutes 0.60 cm³ of PhNHNH₂ (6.1 mmol) was added and the reaction mixture was heated to reflux for one hour. The solution was cooled to room temperature overnight and the resultant yellow-gold precipitate was collected, washed with MeOH (5 cm³) and Et₂ O (10 cm³). The yield of Tc(NNPh)₂ Cl(PPh₃)₂, after drying in vacuo, was 94 mg (0.11 mmol, 80%) based on technetium. This material is only partially soluble in halogenated solvents and insoluble in alcohols. Hence, attempts to purify the complex were only partially successful. Analysis calculated for C₄₈ H₄₀ ClN₄ P₂ Tc: 66.32% C; 4.64% H; 6.45% N. Found: 64.23% C; 4.28% H; 4.87% N.

EXAMPLE 5

The preparation of [Tc(NNPh)Cl(dppe)₂ ][PF₆ ]

Method 1

52 μl of PhNHNH₂ (0.53 mmol) was added to a stirred solution of 80 mg [NBu₄ ][TcOCl₄ ] (0.16 mmol) in 5 cm³ MeOH. After five minutes 253 mg of dppe (0.64 mmol) was added as a solid to the stirred reaction mixture and this was then heated to reflux for one hour. The solution was cooled to room temperature, filtered, and an excess of NH₄ PF₆ (1 g) in 3 cm³ water was added to precipitate an orange compound. This was collected, washed with MeOH (15 cm³) and Et₂ O (30 cm³), and dried in the air. This gave 95 mg of product (0.08 mmol, 50%). The complex could be recrystallised from CH₂ Cl₂ /EtOH. Analysis calculated for C₅₈ H₅₃ ClF₆ N₂ P₅ Tc: 58.97% C; 4.61% H; 2.37% N. Found: 58.92% C; 4.68% H; 2.70% N.

Method 2

A methanolic solution of [NH₄ ][TcO₄ ] was prepared by adding 0.50 cm³ of a 0.29 M aqueous solution of [NH₄ ][TcO₄ ] (0.15 mmol) to 3.0 cm³ of reagent grade MeOH. Phenyl hydrazine (50 μl, 0.51 mmol) was then added to this stirred solution. No reaction appeared to take place until 0.1 cm³ of concentrated HCl was added to the reaction mixture five minutes later. This was immediately followed by the addition of 241 mg dppe (0.81 mmol) as a solid. The reaction mixture was heated to reflux for one hour, cooled to room temperature and filtered to remove excess, unreacted dppe. An excess of [NH₄ ][PF₆ ] was added to the stirred solution as a solid and the resultant suspension was stirred at room temperature overnight. The orange precipitate was then collected, washed with ^(i) PrOH and Et₂ O and dried in vacuo to give 108 mg of [Tc(NNPh)(dppe)₂ Cl][PF₆ ] (0.09 mmol, 60%). The product was identified by comparison of its IR and ¹ H NMR spectra with those obtained from an authentic sample prepared by Method 1.

EXAMPLE 6

The Preparation of [Tc(NNC₆ H₄ Cl)(dppe)₂ Cl][PF₆ ]

This complex was prepared according to Method 2 above from [NH₄ ][TcO₄ ] (0.19 mmol), 129 mg trans-ClC₆ H₄ NHNH₂.HCl (1.07 mmol), 0.1 cm³ concentrated HCl, and 561 mg dppe (1.41 mmol). Yield of [Tc(NNC₆ H₄ Cl) (dppe)₂ Cl][PF₆ ]: 298 mg, 0.24 mmol, 84%. Analysis calculated for C₅₈ H₅₂ Cl₂ F₆ N₂ P₅ Tc. 1/2 CH₂ Cl₂ : 55.99% C; 4.25% H; 2.23% N. Found: 55.73% C; 4.37% H; 1.93% N.

EXAMPLE 7

The reaction of [NBu₄ ][TcOCl₄ ] with Benzoylhydrazine and PPh₃

This reaction was performed according to the Method 1 above for the synthesis of Tc(NNPh)₂ Cl(PPh₃)₂ using 77 mg [NBu₄ ][TcOCl₄ ], 70 mg PhC[O]NHNH₂ (0.51 mmol) and 135 mg PPh₃ (0.51 mmol). After the reaction solution had been heated to reflux for one hour and cooled to room temperature, a light orange compound precipitated and was collected, washed with MeOH (15 cm³) and Et₂ O (30 cm³) and then dried in the air. The compound was identified as TcNCl₂ (PPh₃)₂ by comparison of its IR and NMR spectroscopic characteristics with those of an authentic sample.⁸ The yield was 97 mg (0.14 mmol, 88%). Analysis calculated for C₃₆ H₃₀ Cl₂ NP₂ Tc: 61.12% C; 4.27% H; 1.98% N. Found: 60.66% C; 4.35% H; 2.32% N.

EXAMPLE 8

The reaction between [NBu₄ ][TcOCl₄ ], Benzoylhydrazine and dppe

This reaction was performed according to Method 1 above using 119 mg [NBu₄ ][TcOCl₄ ] (0.24 mmol), 91 mg PhC[O]NHNH₂ (0.67 mmol), and 323 mg dppe (0.81 mmol). The cooled reaction solution was filtered and an excess of [NH₄ ][PF₆ ] was added with stirring. THe orange complex was identified as [TcN(dppe)₂ Cl][PF₆ ] by comparison of its spectroscopic properties with those of an authentic sample.²¹ Yield: 196 mg (0.18 mmol, 75%). Analysis calculated for C₅₂ H₄₈ ClF₆ NP₅ TC: 57.28% C; 4.44% H; 1.28% N. Found: 56.72% C; 4.84% H; 0.87% N.

EXAMPLE 9

The reaction between [NBu₄ ][TcOCl₄ ], H₂ NNH₂ and dppe

This reaction was performed by Method 1 above using 124 mg [NBu₄ ][TcOCl₄ ] (0.25 mmol), 15 μl H₂ NNH₂ (Aldrich, Anhydrous, 0.47 mmol) and 421 mg dppe (1.06 mmol). The reaction solution was heated to reflux for 30 minutes, cooled to room temperature, filtered and an excess of [NH₄ ][PF₆ ] was added to the filtrate with stirring. The resultant orange-brown compound was collected by filtration. Yield: 144 mg (0.20 mmol, 80%). This product was identified as the complex [TcN(dppe)₂ Cl][PF₆ ].

EXAMPLE 10

The Synthesis of TcNNPhMe(PPh₃)₂ Cl₃

108 mg [NBu₄ ][TcOCl₄ ] (0.22 mmol) was dissolved in 10 cm³ dry MeOH and 52 μl MePhNNH₂ (0.44 mmol) was added to the stirred solution. The solution changed from pale green to red-orange immediately. 211 mg PPh₃ (0.80 mmol) was added to the reaction solution and the resulting suspension was heated to reflux for one hour. The resulting suspension was cooled to room temperature and a large amount of a tan precipitate was collected, washed with MeOH (15 cm³) and Et₂ O (30 cm³), and then dried in vacuo. The yield was 108 mg of a complex identified as [Tc(NNPhMe)Cl₃ (PPh₃)₂ ] (0.13 mmol, 59%). Analysis calculated for C₄₃ H₃₈ Cl₃ N₂ P₂ Tc: 60.82% C; 4.51% H; 3.30% N; 12.53% Cl. Found: 60.01% C; 4.17% H; 3.53% N; 12.20% Cl.

EXAMPLE 11

The Preparation of [Tc(NNPhMe)Cl₂ (PMe₂ Ph)₃ ][PF₆ ]

A red-orange solution was prepared by adding 0.10 cm³ MePhNNH₂ (0.85 mmol) to a stirred solution of 1.47 mg [NBu₄ ][TcOCl₄ ] (0.30 mmol) in 4.0 cm³ of MeOH. 0.20 cm³ of PMe₂ Ph was then added to the reaction mixture and this was then heated to reflux for 45 minutes to give a clear orange solution. The solution was then concentrated to approximately 2 cm³ and then 94 mg [NH₄ ][PF₆ ] was added as a solid to the stirred reaction mixture. The precipitate which formed was collected and washed with 7:1 (v/v) Et₂ O--^(i) PrOH. The filtrate was reconcentrated to give a second crop of gold-brown microcrystalline material. The yield was 138 mg of [Tc(NNMePh)Cl₂ (PMe₂ Ph)₃ ][PF₆ ] (0.16 mmol, 54%). Analysis calculated for C₃₁ H₄₀ Cl₂ F₆ N₂ P₄ Tc: 43.93% C; 4.76% H; 3.31% N. Found: 44.53% C; 5.22% H; 3.10% N.

EXAMPLE 12

The Preparation of [Tc^(V) (NNPhMe)Cl(Et₂ NCS₂)₂ ]

A red-orange solution was prepared as described above from 138 mg [NBu₄ ][TcOCl₄ ] (0.28 mmol) and 80 μl MePhNNH₂ (0.68 mmol) in 3 cm³ of MeOH. After this solution had been stirred at room temperature for five minutes, a solution of 200 mg NaS₂ CNEt₂.3H₂ O (0.89 mmol) in 2 cm³ MeOH. The resulting dark red solution was heated to reflux for 30 minutes, cooled to room temperature and the solvent was removed in vacuo to give a red, oily residue. This residue was taken up in 5 cm³ of ^(i) PrOH and this suspension was filtered to give 73 mg of a pale brown powder which was washed with Et₂ O. The filtrate was concentrated to about 1-2 cm³ volume and 50 cm³ Et₂ O was added. The precipitated thus formed was collected and identical to the original material isolated. The overall yield of the complex, identified as [Tc(NNMePh)Cl(Et₂ NCS₂)₂ ] was 111 mg (0.02 mmol, 71%). The complex could be recrystallised from CH₂ Cl₂ /Et₂ O. Analysis calculated for C₁₇ H₂₇ ClN₄ S₄ Tc: 37.12% C; 4.95% H; 10.19% N; 6.44% Cl. Found: 38% C; 5% H; 11% N; 9.4% Cl.

EXAMPLE 13

The Reaction between [NBu₄ ][TcOCl₄ ], MePhNNH₂ and dppe

An orange solution was prepared as described above from 100 mg [NBu₄ ][TcOCl₄ ] (0.20 mmol), 45 μl MePhNNH₂ (0.38 mmol) in 4 cm³ MeOH. 550 mg dppe (1.38 mmol) was then added to this stirred solution as a solid and the resultant suspension was heated to reflux for one hour, cooled to room temperature and filtered to remove unreacted dppe. An excess of [NH₄ ][PF₆ ] was added as a solid to the filtered solution to give a tan precipitate which was washed with MeOH (20 cm³) and Et₂ O (10 cm³). This yielded 121 mg of [Tc(NH)O(dppe)₂ ][PF₆ ] (0.11 mmol, 55%). Analysis calculated for C₅₂ H₄₉ F₆ NOP₅ Tc: 58.27% C; 4.61% H; 1.31% N. Found: 56.90% C; 4.70% H; 1.61% N.

EXAMPLE 14

The Reaction of [NBu₄ ][TcOCl₄ ], Me₂ NNH₂ and dppe

Method 1

An orange-red solution was prepared as described above from 211 mg [NBu₄ ][TcOCl₄ ] (0.42 mmol), 35 μl Me₂ NNH₂ (0.46 mmol) in 5 cm³ MeOH and then 366 mg dppe (1.40 mmol) was added as a solid. The reaction mixture was heated to reflux for one hour, cooled to room temperature and a yellow precipitate was collected (72 mg of [Tc(N₂)(dppe)₂ Cl] (0.07 mmol, 17%). An excess of [NH₄ ][PF₆ ] was added as a solid to the filtrate to give a gold-brown precipitate (137 mg) of [Tc(NNMe₂)Cl(dppe)₂ ][PF₆ ] (0.12 mmol, 29%).

For [Tc(N₂)(dppe)₂ Cl]

Analysis calculated for C₅₂ H₄₈ ClN₂ P₄ Tc: 65.17% C; 5.05% H; 2.92% N. Found: 64.70% C; 5.32% H; 2.07% N.

For [Tc(NNMe₂)Cl(dppe)₂ ][PF₆ ]

Analysis calculated for C₅₄ H₅₂ ClF₆ P₅ Tc: 57.33% C; 4.63% H; 2.48% N. Found: 51.6% C; 4.4% H; 1.8% N.

Method 2

A reaction solution was prepared as for Method 1 from 95 mg [NBu₄ ][TcOCl₄ ] (0.19 mmol), 27 μl Me₂ NNH₂ (0.36 mmol), 333 mg dppe (0.84 mmol) in 5 cm³ MeOH. This reaction mixture was stirred at room temperature for 70 hours. The reaction solution was filtered to remove excess dppe (no yellow precipitate was observed), 65 mg NH₄ PF₆ (0.40 mmol) was added to the filtrate as a solid and the solution was then concentrated in vacuo and the residue was taken up in 5 cm³ CH₂ Cl₂. This solution was filtered to remove undissolved inorganic salts. After filtration, 25 cm³ ^(i) PrOH was added to the filtrate to give 135 mg of a yellow-brown solid which was collected, washed and dried. This was identified by comparison of the IR spectrum of this complex with that of [Tc(NNMe₂)Cl(dppe)₂ ][PF₆ ] prepared by Method 1 (0.12 mmol, 63%).

EXAMPLE 15

The Reaction of [NBu₄ ][TcOBr₄ ], Me₂ NNH₂ and dppe

This was performed by Method 1 for the reaction described above for [NBu₄ ][TcOCl₄ ] using 130 mg [NBu₄ ][TcOBr₄ ] (0.20 mmol), 20 μl Me₂ NNH₂ (0.26 mmol), 247 mg dppe (0.62 mmol) in 5 cm³ MeOH. This gave 55 mg of a yellow complex, Tc(N₂)Br(dppe)₂ (0.06 mmol, 30%). No salts were isolated from the reaction filtrate after the addition of an excess of NH₄ PF₆ to the solution. Analysis calculated for C₅₂ H₄₈ BrN₂ P₄ Tc: 62.22% C; 4.82% H; 2.79% N. Found: 58.48% C; 4.71% H; 2.03% N.

^(99m) Tc Complexes

General: The ^(99m) Tc diazenide and hydrazide (2-) complexes were prepared in a straightforward fashion from the appropriate hydrazine, ^(99m) TcO₄ ⁻ and a suitable ligand. The complex preparations were found to yield the desired cationic products in reasonably high radiochemical purity (see Tables 2-4). The main contaminants in these preparations were the [Tc^(III) Cl₂ (L)₂ ]⁺ cations, as verified by comparison of HPLC and TLC characteristics of these impurities with authentic samples of these Tc^(III) species prepared by a literature method.²² There is some question in the case of the MePhNNH₂ labelled species whether the complexes formed are of the formulation [Tc^(IV) (NNMePh)Cl(L)₂ ]⁺ or [Tc^(V) (NH)O(L)₂ ]⁺. Recent ICES studies on the preparation obtained from the labelling where L=P65 (mmmpe) have shown that the oxidation state of the complex obtained is +4.²³ This indicates that the species present in the MePhNNH₂ preparations are the desired hydrazido (2-) species.

Reagents: The ligands used are given in Table 1. All other reagents used were from commercial suppliers and used as received. [^(99m) TcO₄ ]⁻ was obtained as solutions in physiological saline from Amertec II generators. Reaction products were analyzed by HPLC, TLC and gel electrophoresis as described elsewhere.²⁴ All preparations were performed under an atmosphere of nitrogen gas.

EXAMPLE 16

Complex Preparation: 20-25 μl of hydrazine was added to 2 cm³ of absolute ethanol, then ^(99m) TcO₄ ⁻ (0.2-3.0 GBq) and 10 mg of ligand were added to the solution. This mixture was heated to 120° C. for 30-60 minutes, cooled to room temperature and analyzed. For biodistribution studies the total volume of the preparation was made up to 5 cm³ by the addition of sterile saline solution.

Animal Biodistrution Studies: Six male Sprague Dawley rats were injected while under light ether anaesthesia with 0.1 cm³ of preparation (i.v., tail vein) and half were sacrificed by cervical dislocation while under ether anaesthesia at the appropriate time interval post-injection and dissected. Organs were weighed and their activities measured in an ionisation chamber. For the purposes of calculations blood was assumed to constitute 5.8% of the total body weight, muscle was assumed to be 43% and the lungs were assumed to weigh 1 g.

Biodistribution results are given in Tables 2-4.

                                      TABLE 1                                      __________________________________________________________________________     Ligands used in .sup.99m Tc labelling work                                     Abbreviation                                                                         Structure                      Name                                      __________________________________________________________________________       dmpe                                                                                                                1,2-bis(dimethylphosphino)ethane                                               - dppe                                                                         1,2-bis(diphenylphosphino)ethane                                               - P56                                                                          1,2-bis(di(3-methoxypropyl)                                                  phosphino)ethane                             - PL28                                                                                                             bis((dimethylphosphino)methyl)ether        - P46                                                                                                              1,2-bis((2'-methoxy)ethoxymethyl)                                            methylphosphino)ethane                       - PL34                                                                                                             1,3-bis(dimethylphosphino)-2-                                                ((2-methoxy)ethoxy)propane                   - PL38                                                                                                             1-3-bis(dimethylphosphino)-2,2-bis                                            (2-(2-ethoxy)ethoxy)ethoxymethyl)                                             propane; or  1,3-bis(dimethylphosphin                                          o)-2,2-bis  (2,5,8-trioxadecyl)propan                                          e                                            - PL31                                                                                                             bis((diethylphosphino)methyl)ether         - P53                                                                                                              1,2-bis(di(2'-ethoxy)ethyl)phosphin                                          o  ethane                                    - P65                                                                                                              1,2-bis((methoxymethyl)methyl                                                phosphine)ethane                             - PL37                                                                                                             1,3-bis(dimethylphosphine)-2,2-bis                                            (methoxymethyl)propane                      - PL40                                                                                                             1,3-bis(dimethylphosphino)-2,2-bis                                            (2',5'-dioxaheptyl)propane                  - PL42                                                                                                             1,3-bis(dimethylphosphino)-2,2-bis                                            (ethoxymethyl)propane                       - PL43                                                                                                             1,3-bis(dimethylphosphino)-2,2-bis                                            ((2'-methoxy)ethoxymethyl)  propane         - PL46                                                                                                             1,3-bis(dimethylphosphino)-2-                                                (methoxymethol)-2-((2'methoxy)                                                 ethoxymethyl) propane                        - PL49                                                                                                             4,4-bis((dimethylphosphino)methyl)                                            tetrahydropyran                             - PL50                                                                                                             1,3-bis(dimethylphosphino)-2,2-bis                                            (methoxyethyl)propane                       - P68                                                                                                              1,2-bis(di((2'methoxy)propyl)                                                phosphino)ethane                          __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________     Biodistributions of Phenyldiazenide .sup.99m Tc species in Rats                __________________________________________________________________________     Notebook                                                                            IV23          VI12          VI9                                             Ligand dmpe PL28 P46                                                           RCP (%)                                                                        MEK 60 84 80                                                                   HPLC 40 70 75                                                                Time P.I.                                                                           2      60     2      60     2      60                                     __________________________________________________________________________     Heart                                                                               0.91                                                                              (14)                                                                               0.78                                                                              (03)                                                                               1.12                                                                              (11)                                                                               0.65                                                                              (06)                                                                               0.96                                                                              (04)                                                                               0.80                                                                              (02)                                  Blood 6.98 (71) 1.10 (02) 4.18 (04) 0.46 (04) 7.45 (63) 1.01 (16)                                                        Muscle 22.8 (3.0) 14.0 (3.7)                                                  30.2 (3.0) 27.4 (3.6) 21.4                                                     (3.1) 17.0 (4.0)                      Lung 1.88 (14) 0.86 (10) 1.18 (14) 0.62 (05) 1.41 (27) 0.36 (05)                                                         Liver 22.2 (2.6) 10.5 (8)                                                     17.8 (2.9) 5.95 (57) 26.0                                                      (1.0) 6.92 (1.23)                     S.I. 13.2 (8) 36.7 (4) 13.2 (1.0) 39.6 (2.7) 11.0 (3.2) 44.0 (1.9)                                                       Kidney 11.2 (8) 9.91 (1.25)                                                   9.41 (0.30) 5.90 (06) 9.62                                                     (48) 2.88 (16)                        Bladder 0.11 (03) 11.3 (4) 0.11 (06) 10.9 (5.9) 0.11 (05) 17.8 (2.6)                                                     & Urine                              Brain 0.06 (01) 0.02 (01) 0.04 (00) 0.02 (00) 0.05 (01) 0.01 (00)                                                        H/Bl 1.97 (05) 9.52 (33) 3.97                                                 (32) 21.3 (0.8) 2.05 (29) 13.2                                                 (2.1)                                 H/Li 0.54 (11) 0.93 (11) 0.82 (19) 1.56 (12) 0.58 (06) 1.79 (30)             __________________________________________________________________________     Notebook                                                                            VI31          LH2.17        LH2.30                                          Ligand P46 (HPLC purified) PL42 PL43                                           RCP (%)                                                                        MEK 50 65 26                                                                   HPLC 50 70 50                                                                Time P.I.                                                                           2      60     2      60     2      60                                     __________________________________________________________________________     Heart                                                                               1.05                                                                              (09)                                                                               0.96                                                                              (04)                                                                               1.22                                                                              (30)                                                                               1.19                                                                              (20)                                                                               0.55                                                                              (03)                                                                               0.26                                                                              (03)                                  Blood 7.00 (0.31) 0.78 (08) 28.6 (1.4) 8.99 (2.28) 21.5 (3.5) 1.14 (36)        Muscle 21.0 (3.1) 21.3 (2.3) 18.1 (0.5) 21.3 (0.3) 21.7 (2.4) 10.9                                                      (1.3)                                 Lung 1.33 (14) 0.47 (05) 2.56 (33) 1.57 (32) 1.47 (04) 0.22 (03)                                                         Liver 22.1 (2.0) 4.94 (77)                                                    22.8 (3.2) 14.7 (1.6) 21.4                                                     (1.6) 9.08 (2.03)                     S.I. 11.5 (3.2) 39.8 (0.3) 7.66 (18) 31.8 (2.0) 8.6 (0.5) 45.6 (6.8)                                                     Kidney 11.1 (2.1) 3.31 (17)                                                   5.35 (46) 3.52 (47) 9.19 (74)                                                  2.32 (32)                             Bladder 1.01 (1.49) 17.0 (4.3) 0.06 (01) 2.61 (23) 0.16 (06) 25.4 (4.6)        & Urine                                                                        Brain 0.04 (00) 0.01 (00) --  -- -- --                                         H/Bl 2.37 (12) 18.9 (1.6) 0.59 (12) 2.13 (43) 0.41 (06) 3.83 (1.03)                                                      H/Li 0.66 (12) 2.17 (36) 0.73                                                 (24) 1.12 (26) 0.38 (03) 0.40                                                  (03)                                __________________________________________________________________________     Notebook                                                                            LH2.51        PAH1.26       VI28                                            Ligand P65 PL50 PL38                                                           RCP (%)                                                                        MEK 60 70 86                                                                   HPLC 85 75 80                                                                Time P.I.                                                                           2      60     2      60     2      60                                     __________________________________________________________________________     Heart                                                                               1.20                                                                              (11)                                                                               1.08                                                                              (09)                                                                               0.83                                                                              (09)                                                                               0.65                                                                              (04)                                                                               1.04                                                                              (06)                                                                               0.65                                                                              (09)                                  Blood 5.73 (58) 1.05 (09) 4.38 (25) 0.42 (03) 4.51 (1.36) 0.16 (02)                                                      Muscle 27.8 (8.4) 23.6 (1.7)                                                  18.7 (2.5) 14.9 (2.7) 21.0                                                     (5.1) 16.2 (4.1)                      Lung 1.61 (18) 0.53 (08) 1.02 (12) 0.43 (06) 1.41 (13) 0.35 (11)                                                         Liver 22.0 (1.8) 6.68 (1.19)                                                  34.8 (1.2) 4.35 (30) 28.4                                                      (1.6) 9.27 (35)                       S.I. 11.2 (2.1) 39.8 (4.3) 12.8 (0.7) 57.9 (2.4) 11.5 (2.0) 57.0 (2.8)                                                   Kidney 12.0 (1.2) 3.71 (07)                                                   12.0 (0.30) 6.81 (56) 10.7                                                     (1.9) 4.01 (44)                       Bladder 0.11 (0.05) 9.95 (66) 0.09 (03) 6.76 (65) 0.14 (04) 5.81 (1.46)        & Urine                                                                        Brain --  --  --  --  0.53 (00) 0.00 (00)                                      H/Bl 3.33 (30) 15.8 (1.0) 2.68 (22) 22.2 (0.4) 3.59 (88) 62.5 (7.0)                                                      H/Li 0.81 (12) 2.33 (32) 0.31                                                 (04) 1.27 (96) 0.48 (01) 1.05                                                  (17)                                __________________________________________________________________________

                  TABLE 3                                                          ______________________________________                                         Biodistributions of [Tc.sup.III (NNC.sub.6 H.sub.4 NO.sub.2)(Cl(dmpe).sub.     2 ].sup.+  in Rats                                                                   Notebook    CMAIV78                                                                                            Ligand dmpe                                RCP (%)                                                                        MEK 86                                                                         HPLC 65                                                                      Time P.I.     2                60                                              ______________________________________                                         Heart         1.15   (22)      0.67 (05)                                         Blood 5.68 (66) 0.92 (07)                                                      Muscle 26.2 (7.7) 16.8 (1.2)                                                   Lung 2.27 (15) 1.04 (23)                                                       Liver 22.4 (3.9) 12.3 (0.7)                                                    S.I. 13.0 (3.1) 33.8 (3.2)                                                     Kidney 9.47 (25) 9.47 (33)                                                     Bladder 0.08 (02) 7.28 (1.10)                                                  & Urine                                                                        Brain 0.12 (00) 0.06 (00)                                                      H/Bl 3.00 (49) 11.0 (0.9)                                                      H/Li 0.72 (28) 0.76 (12)                                                     ______________________________________                                    

                                      TABLE 4                                      __________________________________________________________________________     Biodistributions of .sup.99m Tc-hydrazide (2-) species in Rats and Guinea      Pigs                                                                           __________________________________________________________________________     Notebook                                                                            PAH2.14       CMAIV58       CMAVI41                                         Ligand P65 dmpe dmpe (HPLC purified)                                           RCP (%)                                                                        MEK 86 78 83                                                                   HPLC 90 70 73                                                                Time P.I.                                                                           2      60     2      60     2      60                                     __________________________________________________________________________     Heart                                                                               0.95                                                                              (09)                                                                               0.69                                                                              (03)                                                                               1.13                                                                              (13)                                                                               0.80                                                                              (08)                                                                               1.25                                                                              (08)                                                                               0.99                                                                              (15)                                  Blood 4.77 (10) 0.69 (13) 7.84 (47) 1.05 (11) 7.95 (21) 1.05 (21)                                                        Muscle 26.1 (5.8) 20.2 (2.7)                                                  27.9 (4.9) 20.6 (3.2) 26.3                                                     (5.2) 19.3 (4.9)                      Lung 1.58 (0.36) 0.33 (02) 2.36 (37) 1.14 (07) 2.40 (0.21) 1.28 (20)                                                     Liver 22.8 (1.4) 9.23 (26)                                                    22.2 (0.6) 11.6 (1.6) 21.1                                                     (1.7) 10.8 (1.9)                      S.I.     10.5 (2.2) 30.6 (3.4) 11.9 (3.2) 31.1 (4.5)                           Kidney 7.76 (12) 1.95 (15) 9.95 (1.40) 11.1 (0.4) 10.8 (0.6) 11.6 (1.3)        Bladder     0.08 (01) 6.84 (77) 0.12 (07) 4.70 (93)                            % Urine                                                                        Brain     0.05 (01) 0.03 (01) 0.07 (01) 0.04 (01)                              H/Bl 3.25 (27) 15.0 (3.4) 2.43 (12) 12.2 (1.4) 2.27 (21) 14.2 (2.4)                                                      H/Li 0.64 (06) 1.11 (02) 0.78                                                 (13) 1.06 (13) 0.82 (04) 1.30                                                  (41)                                __________________________________________________________________________     Notebook                                                                            CMAVI15       CMAVI36       CMAVI36                                         Ligand P46 P46* (HPLC purified) P46 (HPLC purified) RATS                       RCP (%)                                                                        MEK 64 54 54                                                                   HPLC 65 53 53                                                                Time P.I.                                                                           2      60     2      60     60                                            __________________________________________________________________________     Heart                                                                               0.81                                                                              (07)                                                                               0.58                                                                              (04)                                                                               0.96                                                                              (12)                                                                               0.65                                                                              (03)                                                                               0.97  (06)                                      Blood 7.10 (0.51) 0.50 (05) 10.1 (1.7) 0.89 (12) 0.27 (02)                     Muscle 28.4 (2.5) 18.4 (2.5) 21.9 (3.3) 28.5 (2.2) 20.0 (1.2)                  Lung 1.33 (09) 0.30 (07) 1.30 (05) 0.51 (11) 0.36 (10)                         Liver 23.3 (0.5) 7.23 (70) 15.9 (1.1) 5.18 (36) 8.29 (67)                      S.I. 9.38 (3.20) 44.8 (2.6) 11.3 (1.2) 15.0 (7.1) 43.6 (2.2)                   Kidney 9.37 (52) 2.13 (10) 13.0 (1.6) 11.0 (0.3) 4.05 (66)                     Bladder 0.18 (10) 19.2 (1.6) 0.22 (17) 10.6 (1.1) 12.7 (1.0)                   & Urine                                                                        Brain 0.04 (02) 0.51 (13)                                                      H/Bl 1.65 (08) 16.5 (1.0) 2.89 (53) 11.8 (2.1) 58.7 (1.0)                      H/Li 0.48 (03) 1.01 (13) 0.88 (10) 1.89 (0.22) 1.68 (14)                     __________________________________________________________________________      *In Guinea Pigs                                                          

EXAMPLES 17-19

All reactions were performed under an atmosphere of dinitrogen using predried, distilled solvents unless noted otherwise. [Bu₄ N][TcOCl₄ ] was prepared by the literature procedure.²⁸

EXAMPLE 17

Technetium Diazenido-Starting Materials

a) [TcCl(NNC₆ H₄ Cl)₂ (PPh₃)₂ ] 9

Method 1. From [Bu₄ N][TcOCl₄ ]

[Bu₄ N][TcOCl₄ ] (0.134 g, 0.268 mmol), 4-ClC₆ H₄ NHNH₂.HCl (0.120 g, 0.67 mmol, 2.5 equivalents), Et₃ N (0.09 ml, 0.67 mmol), and PPh₃ (0.211 g, 0.804 mmol , 3 equivalents) in dry methanol (5 ml) were stirred for 2 hours at room temperature. The khaki solid was collected by filtration, washed with methanol and ether and dried. (yield 0.134 g, 53%). The product could be recrystallised from CH₂ Cl₂ /MeOH yielding bright orange crystals. (Found: C, 61.23; H, 3.98; N, 6.05; Cl, 11.74. TcC₄₈ H₃₈ N₄ P₂ Cl₃ requires C, 61.45; H, 4.08; N, 5.97; Cl, 11.34%). HPLC retention time 9.4 minutes, single species. v_(max). (KBr plates, nujol mull) 1600, 1555 cm⁻¹ (NN). ³¹ P NMR (CDCl₃) 30.27 ppm singlet.

Method 2. From [NH₄ ][TcO₄ ]

Aqueous [NH₄ ][TcO₄ ] (0.5 ml, 0.181 mmol) was evaporated to dryness in vacuo. ClC₆ H₄ NHNH₂.HCl (0.142 g, 0.793 mmol) in dry methanol (2.5 ml) was added with stirring to give an orange solution after 10 minutes. Solid PPh₃ (0.204 g, 0.778 mmol) was added and the mixture heated under reflux for 1.5 hours. After cooling to room temperature the khaki solid was collected by filtration and washed with ether (yield 0.113 g, 67%). The product could be crystallised from CH₂ Cl₂ /MeOH to yield an orange crystalline solid which has an identical IR spectrum to an authentic sample of 9 prepared from (TcOCl₄ ]⁻.

b) [Tc(NNC₆ H₄ CH₃)₂ (PPh₃)₂ ] 10

[Bu₄ N][TcOCl₄ ] (0.178 g, 0.356 mmol), CH₃ C₆ H₄ NHNH₂.HCl (0.282 g, 1.78 mmol, 5 equivalents), Et₃ N (0.25 ml, 1.78 mmol), and PPh₃ (0.280 g, 1.07 mmol, 3 equivalents) were stirred in dry methanol (5 ml) overnight to give a khaki suspension. The product was collected by filtration, washed with ether and dried (yield 0.122 g, 40%). HPLC retention time 10.4 minutes, one major species. Analysis on the crude material gave (Found: C, 64.1; H, 4.6; N, 5.9; Cl, 3.53. TcC₅₀ H₄₄ N₄ P₂ Cl requires C, 66.93; H, 4.94; N, 6.24; Cl, 3.95%). ¹ H NMR (CDCl₃) 2.29[6H, s, 2×CH₃ ], 6.5-8.0 [38H, m, phenyl H]. ³¹ P NMR (CDCl₃) 28.6 ppm singlet. v_(max). 1620, 1570, 1535 cm⁻¹ (NN). The product may be recrystallised from CH₂ Cl₂ /MeOH.

c) [TcCl₂ (NNC₆ H₄ NO₂)(PPh₃)₂ ] 11

[Bu₄ N[TcOCl₄ ] (0.152 g, 0.304 mmol), O₂ NC₆ H₄ NHNH₂ (0.116 g, 0.76 mmol, 2.5 equivalents), and PPh₃ (0.239 g, 0.912 mmol, 3 equivalents) in dry methanol (5 ml) were stirred overnight to give a pale orange solid which was collected by filtration (yield 0.223 g, 77%). This was recrystallised from CH₂ Cl₂ /MeOH to give a lime-green solid (0.151 g, 52%). v_(max). 1620, 1600 (NN), 1555 (NO₂), 1335 (NO₂) cm⁻¹. ¹ H NMR (CDCl₃) 3.4 [MeOH], 7.0-8.0[phenyl H]. ³¹ P NMR (CDCl₃) 30.0 ppm singlet. HPLC retention time 10.4 minutes. (Found: C, 57.65; H, 4.18; N, 4.94; Cl, 8.60. Found: C, 57.42; H, 4.24; N, 4.95; Cl, 7.95. TcC₄₃ H₃₈ N₃ Cl₂ O₃ P₂ requires C, 58.92; H, 4.37; N, 4.79; Cl, 8.09%).

EXAMPLE 18

Substitution Chemistry of the Technetium Diazenido-Starting Materials

a) [TcCl(NNC₆ H₄ Cl)(dppe)₂ ][BPh₄ ] 12

9 (0.098 g, 0.104 mmol) and dppe (0.104 g, 0.26 mmol, 2.5 equivalents) in methanol-toluene (1:1, 4 ml) were heated under reflux for 3 hours to give a dark orange solution. Solid NaBPh₄ (0.035 g, 1 equivalent) was added with stirring to precipitate an orange solid. The product was collected by filtration (yield 0.117 g, 77%). The crude product could be recrystallised from CH₂ Cl₂ /ether. (Found: C, 70.55; H, 5.34; N, 2.17; Cl, 4.72. TcC₈₀ H₇₂ N₂ BP₄ Cl₂ requires C, 70.34; H, 5.31; N, 2.05; Cl, 5.19%). HPLC retention time 14 minutes. v_(max). 1575, 1665 cm⁻¹ (NN). ¹ H NMR (CDCl₃) 2.68[8H, broad m, 2×--CH₂ CH₂ --], 6.5-7.5[64H, broad unresolved m, phenyl H].

b) [TcCl(NNC₆ H Cl)(dppe)₂ ][PF₆ ] 12a

This was prepared in an analogous fashion to 12 using 9 (0.101 g, 0.107 mmol) and dppe (0.107 g, 0.269 mmol) in methanol/toluene (1:1, 4 ml) under reflux for 1 hour. [NH₄ ][PF₆ ] (0.018 g, 0.110 mmol) was added with stirring to the filtered reaction mixture to give 12a (yield 0.059 g, 43%). This could be recrystallised from CH₂ Cl₂ /MeOH (Found: C, 55.44; H, 4.27; N, 2.48; Cl, 6.35. TcC₅₈ H₄₄ N₂ P₅ Cl₂ F₆ requires C, 57.68; H, 3.67; N, 2.32; Cl, 5.87%).

c) [TcCl(NNC₆ H₄ NO₂)(dppe)₂ ][BPh₄ ] 13

11 (0.051 g, 0.06 mmol) and dppe (0.060 g, 0.151 mmol, 2.5 equivalents) in methanol/toluene (1:1, 3 ml) were heated under reflux for 1 hour to give an orange-red solution. After cooling to room temperature solid NaBPh₄ (0.02 g, 1 equivalent) was added with stirring to precipitate the product as an orange solid. This was collected by filtration and washed with MeOH and Et₂ O (yield 0.06 g, 72%). The product was recrystallised from CH₂ Cl₂ /Et₂ O (yield 0.042 g, 50%) as an orange crystalline solid. v_(max). 1645s, 1600w (NN), 1570 (NO₂), 1340 (NO₂) cm⁻¹. HPLC retention time 14.2 minutes, single peak. (Found: C, 67.65; H, 5.12; N, 2.93; Cl, 4.14. TcC₈₂ H₇₂ N₃ O₂ Cl-P₄ B.1/2CH₂ Cl₂ requires C, 68.66; H, 5.10; N, 2.91; Cl, 4.91%).

d) [Tc(NNC₆ H₄ Cl)(S₂ CNMe₂)₂ (PPh₃)] 14

9 (0.139 g, 0.148 mmol) and NaS₂ CNMe₂ (0.08 g, 0.444 mmol, 3 equivalents) in absolute ethanol (2 ml) were heated under reflux for 1.5 hours. The orange solid was collected by filtration after cooling (yield 0.072 g) and redissolved in CH₂ Cl₂ before passage down a Fluorsil column eluting the orange band with CH₂ Cl₂. This eluate was evaporated to dryness and the residue recrystallised from CH₂ Cl₂ /Et₂ O to give dark orange crystals (yield 0.072 g, 66%). HPLC retention time 13.6 minutes, single species. (Found: C, 45.82; H, 4.09; N, 6.79; Cl, 6.25. Found: C, 45.99; H, 4.04; N, 6.77. TcC₃₀ H₃₁ N₄ ClS₄ P.1/2CH₂ Cl₂ requires C, 46.74; H, 4.11, N, 7.15; Cl, 9.05. TcC₃₀ H₃₁ N₄ ClS₄ P.1/4CH₂ Cl₂ requires C, 47.65; H, 4.16, N, 7.35; Cl, 6.97%). ¹ H NMR (CDCl₃) 2.92[3H, s, CH₃ ], 3.06[3H, s, CH₃ ], 3.31[3H, s, CH₃ ], 3.39[3H, s, CH₃ ], 5.27[CH₂ C₂ ], 6.8-7.7[19H, m, phenyl H]. ³¹ P NMR (CDCl₃) no signal was observed in this sample at room temperature.

e) [TcCl(NNC₆ H₄ Cl) (maltol) (PPh₃)₂ ] 15

9 (0.145 g, 0.155 mmol) and maltol (0.059 g, 0.465 mmol, 3 equivalents) in absolute ethanol (2 ml) were heated under reflux for 2 hours. After cooling to room temperature the orange product was collected by filtration and washed with ethanol. The product was recrystallised from CH₂ Cl₂ /ether (yield 0.03 g, 21%) as dark orange crystals. (Found: C, 59.68; H, 4.11; N, 3.03; Cl, 7.73. TcC₄₈ H₃₉ N₂ Cl₂ O₃ P₂ requires C, 62.41; H, 4.23; N, 3.03, Cl, 7.68%). v_(max). 1615s, 1560 cm⁻¹. ¹ H NMR (CDCl₃) 2.21[3H, s, CH₃ ], 5.63[1H, d, J³ _(HH) =4 Hz, C═CH], 6.92[1H, d, J³ _(HH) =4 Hz, C═CH], 7.0-8.0[34H, m phenyl H]. ³¹ P NMR (CDCl₃) 30.0 ppm singlet. HPLC retention time 10 minutes.

f) [Tc(NNC₆ H₄ Cl)(salen)(PPh₃)] 16

9 (0.100 g, 0.107 mmol), salenH₂ (0.032 g, 0.119 mmol, 1.1 equivalents), and Et₃ N (0.40 ml, 0.259 mmol, 2.2 equivalents) in dry methanol/toluene (1:1, 3 ml) were heated under reflux for 2 hours. After cooling, addition of ether gave a khaki-green solid which was collected by filtration, washed with ether and dried (yield 0.052 g, 63%). The product could be recrystallised from CH₂ Cl₂ /heptane as very dark green crystals. (Found: C, 61.77; H, 4.41; N, 7.17; Cl, 4.77. TcC₄₀ H₃₃ N₄ PO₂ Cl requires C, 62.63; H, 4.34; N, 7.30; Cl, 4.62%). v_(max). 1600, 1610, 1620 (NN), 1540 (C═N) cm⁻¹. ¹ H NMR (CDCl₃) 4.0[4H, broad m, --CH₂ CH₂ --], 6.0-7.6[27H, broad m, phenyl H], 8.14[2H, s, N═CH]. ³¹ P NMR (CDCl₃) no signal was observed at room temperature. HPLC retention time 11.6 minutes.

g) [Tc(NNC₆ H₄ C₁)₂ (N₂ S₂)]_(x) 17 N₂ S₂ =(HSCH(Me)CONHCH₂ --)₂

9 (0.083 g, 0.088 mmol), N₂ S₂ (0.023 g, 0.097 mmol, 1.1 equivalents), and Et₃ N (0.05 ml, 0.34 mmol, 4 equivalents) in dry methanol (2 ml) were heated under reflux for 1 hour to give a dark brown-green solution. The solvent was removed in vacuo and the brown oil triturated with isopropanol to give a dark brown solid product (yield 0.011 g). The product was too insoluble for satisfactory recrystallisation and analysis by NMR, but appeared to be diamagnetic. HPLC retention time 12.2 minutes. (Found: C, 40.36; H, 4.40; N, 9.19; Cl, 11.97. TcC₂₀ H₂₄ N₄ Cl₂ S₂ O₂ requires C, 40.96; H, 4.12; N, 9.55; Cl, 12.09%).

EXAMPLE 19 Technetium Imido Complexes

[TcCl₂ (NC₆ H₄ CO₂)(PPh₃)₂ ] 18

Method 1. From [NH₄ ][TcO₄ ]

Aqueous [NH₄ ][TcO₄ ] (1 ml, 0.343 mmol), 2-HO₂ CC₆ H₄ NH₃ Cl (2-carboxyaniline hydrochloride) (0.298 g, 1.715 mmol, 5 equivalents), and PPh₃ (0.360 g, 1.372 mmol, 4 equivalents) in reagent grade methanol (10 ml) were stirred overnight to give a bright green precipitate. The product was collected by filtration, washed with MeOH, ether and dried in vacuo (yield 0.139 g, 50%). (Found: C, 63.30; H, 4.44; N, 1.77. TcC₄₃ H₃₄ NO₂ P₂ C₂ requires C, 62.33; H, 4.14; N, 1.67%). The product was soluble in DMF and CH₂ Cl₂.

Method 2. From [Bu₄ N][TcOCl₄ ]

[Bu₄ N][TcOCl₄ ] (0.262 g, 0.525 mmol), anthranilic acid (0.72 g, 5.25 mmol, 10 equivalents), and PPh₃ (0.48 g, 1.84 mmol, 3.5 equivalents) in absolute ethanol (20 ml) were heated under reflux for 2 hours. The hot solution was filtered (air) and taken to dryness in vacuo. The residue was then triturated with ether and the solid green product isolated after filtration was recrystallised from EtOH/hexane (yield 0.114 g, 26%). ³¹ P NMR (DMSO) 31.2 ppm singlet.

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We claim:
 1. A ^(99m) Tc complex which contains the moiety Tc═NR, Tc--N═NY or Tc(--N═NY)₂ and a synthetic organic ligand which confers biological target-seeking properties on the technetium complex,where R is an aryl group, a substituted or unsubstituted alkyl group or the group--NR¹ R² ; Y is an aryl group or a substituted or unsubstituted alkyl group; and R¹ and R² are H, aryl groups or substituted or unsubstituted aliphatic or cyclic alkyl groups, and are the same or different provided that both are not hydrogen.
 2. The ^(99m) Tc complex of claim 1 which also contains a phosphine or arsine bound to the technetium, where the phosphine and arsine has the general formula:

    Q.sub.2 B(CD.sub.2).sub.n BQ.sub.2

where Q is H, an aryl group or a substituted or unsubstituted alkyl group; B is P or As; CD₂ is a substituted methylene group; and n is 1, 2, 3 or
 4. 3. A method of preparation of the ^(99m) Tc complex of claim 1, which comprises the derivatization of a technetium oxo-containing species by condensation with a hydrazine, an amine, an isocyanate, a sulphinylamine or a phosphinimine.
 4. A method of preparation of the ^(99m) Tc complex of claim 1, which comprises the reaction of a hydrazine or amine with a technetium complex containing technetium-halogen bonds.
 5. A radiopharmaceutical which includes a ^(99m) Tc complex as claimed in claim
 1. 6. A radiopharmaceutical composition which comprises the ^(99m) Tc complex of claim 1, wherein the biological target seeking properties of the complex are determined by the ligands present, or the substituents R and Y, or a combination of the ligands present and the substituents R and Y. 